PROJECT SUMMARY/ABSTRACT Natural products have been notably at the forefront of most approaches to combating many infectious diseases. Many of the natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. Recently we have developed a series of novel antimalarial chemical entities inspired by the prodiginine and tambjamine natural products that meet the following key criteria: 1) potent activities against liver stage and blood stage malaria parasites, as well as inhibition of gamete formation; 2) orally efficacious; 3) curative in a single dose; 4) fast-acting; 5) long duration of coverage; and 6) unique chemotype as compared to existing antimalarials likely operate by a novel mechanism(s) of action. The ability to combat multiple stages of the infection with the potential of transmission blocking represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as a renewed malaria eradication effort proceeds. Our proposed work in this application seeks to develop novel, potent, safe, and inexpensive antimalarial drugs for both prevention and treatment of malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce lead candidates for full preclinical testing that retain the broad-spectrum features and demonstrate enhanced efficacy, safety and pharmacokinetic profiles that warrant further development.